T-cell acute lymphoblastic leukemia (T-ALL), which comprises 10% to 15% of ALL cases in pediatric patients, is especially common in teenagers and accounts for 25% of ALL cases in adults. Despite significant advances in long-term event-free survival, current treatments for T-ALL are often toxic to normal tissues, producing serious acute and delayed sequelae in a substantial fraction of patients. The central hypothesis for this research is that in-depth knowledge of multi-step pathways of molecular pathogenesis is needed to propel progress toward personalized medicine for T-ALL. An important long-term goal is to find genes encoding new targets and molecular pathways for the development of more specific and less toxic drugs for the treatment of T-ALL. This goal will be achieved through three specific aims. In Aim 1, we will build on work conducted during the last funding period of this project to identify oncogenic pathways and therapeutic targets in high risk T-ALLs with the absence of biallelic TCRy chain deletions (ABD subtype) and PTEN loss. We will conduct BH3-profillng to specifically target anti-apoptotic pathways and also test mTOR inhibitors to improve therapy for the high risk ABD subgroup. In Aim 2, we will build on our exciting new preliminary data to determine the mechanisms of TYK2 pathway dependence and analyze selective pathway inhibitors in T-ALL. We recently discovered that the majority of human T-ALLs depend on TYK2 tyrosine activity for growth an survival, and In this Aim we will interrogate this pathway in detail to develop potent inhibitors that specifically target T-ALL cells. In Aim 3, we will pursue our discovery during the last funding period that LEF1 Is a tumor suppressor in T-ALL to define the mechanisms through which loss of LEF1 contributes to T-ALL using zebrafish and primagraft T-ALL models. Each of these Alms involves numerous opportunities to interact closely with other projects in this program, with the ultimate goal of bringing novel targeted therapies to the bedside for children and adults with T-ALL.